Parenteral administration of nimodipine

Abstract

A method of providing an IV nimodipine infusion regimen using a solubilized nimodipine solution suitable for IV administration is disclosed. The IV nimodipine infusion regimen provides a constant infusion rate over a (entire) 24-hour period, supplemented with nimodipine in a higher infusion amount at a set interval to replicate 24-hour AUC and Cmax for oral nimodipine doses.

Description

Technical Field

[0001] The present invention provides a stable, preservative-free nimodipine parenteral solution suitable for continuous intravenous (IV) administration via an IV nimodipine infusion pump. The parenteral solution composition consists of nimodipine (at a concentration range of about 0.01 to about 5 mg / ml), a hydrophilic surfactant, and a cosolvent (preferably ethanol). The final concentration of ethanol in the administered formulation is preferably less than about 2% w / v. Background Art

[0002] Nimodipine is a lipid-soluble substituted 1,4-dihydropyridine with vasodilatory properties, suitable for the prevention and treatment of ischemic neurological deficits caused by cerebral vasospasm after subarachnoid hemorrhage (SAH). Currently, nimodipine is the first-line treatment for ischemic brain injury. In humans, nimodipine is rapidly absorbed after oral administration and peak concentrations are usually reached within one hour. The terminal elimination half-life is approximately 8 to 9 hours, but the earlier elimination rate is much faster, equivalent to a half-life of 1-2 hours; as a result, frequent (every 4 hours) dosing is required. Nimodipine is eliminated almost entirely in the form of metabolites, and less than 1% is collected in the urine as unchanged drug. A number of metabolites have been identified, all of which are inactive or have considerably lower activity than the parent compound. Due to the high first-pass metabolism of nimodipine, the bioavailability after oral administration averages 13%. The bioavailability is significantly increased in patients with cirrhosis, C max This is approximately twice that of normal patients, which requires a reduction in the dose for this group of patients.

[0003] The products currently approved for the U.S. market are oral solid and liquid dosage forms of nimodipine. Liquid-filled capsules (Bayer Pharmaceuticals Corp.) and equivalent generic versions are marketed. The capsules and their generic versions each contain 30 mg of nimodipine and are usually administered in a dose of two capsules of 60 mg and once every 4 hours. In the case of a patient who loses consciousness or is unable to swallow, the contents of the nimodipine capsule are extracted by a syringe and administered through an intraoral or intranasal (e.g., nasogastric) tube. The physician administering the dose may accidentally or due to improper operation cause the dose extracted from the capsule to be less than the entire amount of the liquid dose, thereby causing a huge risk of incomplete medication and bringing excessive burdens to medical staff. The relatively small dose volume and high drug concentration of the drug involved in the commercially available capsules exacerbate incomplete medication. Therefore, if the physician fails to administer the entire amount of the high-concentration, small-volume liquid from the commercially available capsule, a significant underdose of nimodipine may result. In addition, the FDA has pointed out in a warning related to oral administration of nimodipine through a nasogastric tube that the preparation in the capsule is extracted using an intravenous syringe because the standard needle does not match the oral syringe. The use of an intravenous syringe to extract the nimodipine preparation from the capsule increases the chance of inadvertently administering the drug intravenously rather than through the mouth or nasogastric tube.

[0004] In order to quickly and effectively treat or control disease progression after SAH, intravenous administration of nimodipine is generally preferred. Intravenous (IV) nimodipine is approved in Europe and is marketed in Europe under the trade name Marketed by Bayer. The commercially available injectable nimodipine (Bayer's ) contains large amounts of organic solvents - approximately 23.7% ethanol and 17% polyethylene glycol 400. The large amount of ethanol in Nimotop is harmful to those with alcoholism or impaired alcohol metabolism, as well as pregnant or breastfeeding women. In addition, high concentrations of ethanol may cause pain and irritation at the injection site. IV Nimotop is most often given as a continuous infusion for up to three weeks. Because of the high alcohol content in Bayer's IV Nimotop solution, it is diluted by co-infusion of saline and dextrose in a three-way stopcock.

[0005] Nimodipine is poorly soluble in water and is therefore difficult to formulate into an aqueous injectable. This is why the Nimotop IV infusion solution uses up to 23.7% alcohol as a co-solvent to dissolve nimodipine.

[0006] U.S. Pat. No. 5,114,956 describes a parenteral preparation containing nimodipine, which contains 0.01-0.4% by weight of nimodipine relative to 100 parts by weight of a solvent, the solvent consisting of: 30-70% by weight, preferably 45-70% by weight of water; 15-40% by weight, preferably 15-30% by weight of propylene glycol and / or polyethylene glycol, which preferably have an average molecular weight of 200, 400 and 600; 15-30% by weight, preferably 15-25% by weight of ethanol; and, where appropriate, conventional adjuvants and / or additives.

[0007] Through its Adverse Event Reporting System (AERS) and other sources, including published literature, the FDA has identified 31 nimodipine errors between 1989 and 2009, 25 of which involved the contents of oral capsules administered intravenously. Four patients who received nimodipine intravenously died, while five others suffered severe reactions and one patient suffered permanent injury, according to the agency.

[0008] There is an unmet medical need for a dosage form of nimodipine that is easy to administer to patients who have difficulty or are unable to swallow, as well as to patients who are unconscious or taking concomitant medications that could cause drug-drug interactions. There is also an urgent need to eliminate serious, life-threatening medication errors caused by inappropriate administration of medications. Summary and purpose of the invention

[0009] It is an object of the present invention to replace an oral nimodipine treatment regimen with an IV nimodipine infusion regimen that can provide human patients with daily plasma nimodipine exposure equivalent to an oral regimen of 60 mg or 30 mg nimodipine administered every 4 hours.

[0010] Another object of the present invention is to use an IV nimodipine infusion regimen over a 24 hour period that replicates or mimics the 24 hour area under the curve (AUC) and C of a 60 mg nimodipine oral capsule administered at 4 hour intervals over a 24 hour period. max .

[0011] Another object of the present invention is to use an IV nimodipine infusion regimen administered over a 24 hour period that replicates or mimics the 24 hour area under the (plasma concentration) curve (AUC) and maximum plasma concentration (C) of a 30 mg nimodipine oral capsule administered at 4 hour intervals over a 24 hour period. max ).

[0012] Another object of the present invention is to reduce the between-subject variability of plasma nimodipine concentrations by using the present IV infusion regimen compared to the oral route of nimodipine administration.

[0013] Another object of the present invention is to provide an IV nimodipine dosing regimen having a more reproducible concentration-time profile over the course of a 24-hour period, less diurnal variation between morning and evening concentrations, and a more rapid response to dose adjustments.

[0014] It is another object of the present invention to provide an IV nimodipine dosing regimen that has less diurnal variation between morning and evening concentrations.

[0015] Another object of the present invention is to provide an IV nimodipine dosing regimen that provides similar AUC and C max The oral dosing regimen is faster.

[0016] It is another object of the present invention to provide an IV nimodipine dosing regimen that is less likely to be compromised by reduced or lost gastrointestinal motility or patient coma.

[0017] In accordance with the above objects and other objects, the present invention relates in part to the administration of an IV nimodipine infusion regimen that provides a substantially constant infusion rate over a (whole) 24 hour period, supplemented with higher infusion amounts of nimodipine at set intervals to replicate the 24 hour AUC and C of an oral nimodipine dose. max However, the present invention is not limited to a single 24-hour infusion. It is contemplated that the 24-hour nimodipine dosing regimen may be repeated as needed.

[0018] In a preferred embodiment, 0.15 mg / hour of nimodipine is infused by IV administration over a 24-hour period, supplemented with 4 mg of nimodipine as a 30-minute infusion at 4-hour intervals, to replicate the 24-hour area under the curve and 24-hour C of 60 mg of nimodipine administered as an oral capsule at 4-hour intervals over a one-day course of treatment. max In other words, such dosing can be achieved by, for example, 8.30 mg / hour for 30 minutes, followed by 0.15 mg / hour for about 3.5 hours; or in other words, by administering a 4.15 mg bolus dose over 30 minutes, followed by 0.15 mg / hour for about 3.5 hours.

[0019] In certain preferred embodiments, the IV nimodipine treatment regimen is achieved by a constant infusion of nimodipine over a 24-hour period (e.g., about 0.15 mg / hour) supplemented with a 30-minute infusion of about 4 mg nimodipine at 4-hour intervals using a programmable infusion pump or by using 2 infusion pumps with controllable delivery rates that replicates the 24-hour area under the curve and 24-hour C of the desired dose of nimodipine administered orally (e.g., as an oral capsule) at 4-hour intervals over the course of a day. max .

[0020] In certain embodiments, the invention relates in part to an IV nimodipine infusion wherein a constant infusion of about 0.15 mg / hour of nimodipine over a 24 hour period is supplemented with a 30 minute infusion of about 4 mg of nimodipine at 4 hour intervals that replicates the 24 hour area under the curve and 24 hour C of 60 mg nimodipine administered as an oral capsule at 4 hour intervals over the course of a day. max . Thus, 27.6 mg of IV nimodipine provides a 24-hour plasma nimodipine exposure equivalent to 360 mg of oral nimodipine, and provides a similar pulsatile concentration-time curve. The delivery rate of IV nimodipine infusion can be proportionally adjusted in direct proportion to the target oral dose of the proposed treatment. For example, the infusion rate can be halved (0.075 mg / hour continuous + 2 mg in 30 minutes at 4 hour intervals) to provide an equivalent plasma exposure of 30 mg every 4 hours as an oral nimodipine capsule.

[0021] The IV nimodipine IV infusion of the present invention can be achieved by using 2 infusion pumps, one running continuously at a slow rate, and the other opened at 4 hour intervals for 30 minutes and then closed, wherein the 2 pumps deliver their infusate to a shared infusion tube by means of a 3-way valve. Alternatively, a single programmable infusion pump with a preset speed can be used to deliver two infusion rates (4.075 mg / hour for 30 minutes, followed by 0.15 mg / hour for 3.5 hours, repeating the sequence multiple times as needed). Alternatively, a single programmable infusion pump can be used to continuously provide nimodipine at a slow rate, and the dose administered at intervals of about 4 hours can be manually administered.

[0022] The IV nimodipine dosing regimen of the present invention provides a more reproducible nimodipine plasma profile over the course of a day, with less diurnal variation between morning and evening concentrations, and a more rapid response to dose adjustments if drug-related side effects (e.g., hypotension) are found during a course of treatment. In addition, IV delivery is less likely to be compromised by reduced or lost gastrointestinal motility or patient coma.

[0023] The present invention also relates to a method for treating a human patient suffering from a disease selected from aneurysm, subarachnoid hemorrhage, vasospastic angina, Prinzmetal angina, stable angina, acute myocardial infarction, myocardial arrest, arrhythmia, systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery surgery and hypertrophic cardiomyopathy, comprising continuously infusing an intravenous nimodipine solution according to the present invention over a period of about three weeks. The nimodipine infusion regimen can be administered, for example, by intravenous bolus and as an intravenous infusion. In certain embodiments, the IV nimodipine dosing regimen can be contained in an infusion set and a bag. In a further embodiment, the infusion bag is covered with an ultraviolet (UV) protective bag to further protect nimodipine from photodegradation. In other preferred embodiments, the nimodipine formulation is administered as a continuous infusion. In the method of the present invention, the first-pass metabolism of the liver is minimized and bioavailability is improved. Thus, consistent nimodipine levels are maintained in the plasma and CSF of a (eg, human) patient.

[0024] In certain preferred embodiments, the IV nimodipine dosing regimen can be administered as a pharmaceutical composition containing a nimodipine base or any pharmaceutically acceptable salt as an active ingredient for continuous parenteral administration. The IV nimodipine dosing regimen can be a sterile preservative-free premix, ready for infusion without further dilution prior to administration. Alternatively, the IV nimodipine dosing regimen can be in the form of a concentrated injectable solution, which can be diluted in an appropriate medium (e.g., normal saline) to a solution for administration by infusion.

[0025] The present invention relates in part to a method of providing an IV nimodipine infusion regimen in humans, comprising administering (i) a continuous nimodipine infusion over a period of at least 24 hours, supplemented with (ii) a higher bolus dose of nimodipine at set intervals over a period of at least 24 hours, such that the 24-hour AUC and Cmax of nimodipine in the dosing regimen are equivalent to oral nimodipine doses. The time period for administering the IV nimodipine infusion regimen exceeds 24 hours. In certain embodiments, the continuous (constant) nimodipine infusion is an IV administration of about 0.15 mg / hour of nimodipine infused over a 24-hour period, supplemented with a higher bolus dose of nimodipine of more than about 4 mg of nimodipine infused over about 30 minutes at intervals of about 4 hours, such that the IV nimodipine infusion regimen is equivalent to the 24-hour area under the curve and 24-hour Cmax of 60 mg nimodipine oral capsules administered at intervals of about 4 hours over a course of one day. This can be achieved by (i) using a single programmable infusion pump, or (ii) using two infusion pumps with controllable delivery rates to provide a constant infusion of nimodipine over a 24-hour period, or (iii) using a single programmable infusion pump to provide a constant infusion of nimodipine over a 24-hour period, supplemented with manually administered bolus doses of nimodipine at intervals of about 4 hours, supplemented with nimodipine infused over 30 minutes at intervals of about 4 hours, such that the IV nimodipine infusion regimen is equivalent to the 24-hour area under the curve and 24-hour Cmax of the required dose of nimodipine administered orally (e.g., as an oral capsule) at intervals of about 4 hours over a course of one day. In certain preferred embodiments, the IV nimodipine infusion regimen is such that 27.6 mg of IV nimodipine provides a 24-hour plasma nimodipine exposure equivalent to 360 mg of oral nimodipine, and provides a similar pulsatile concentration-time curve. In addition, the IV nimodipine infusion regimen can be scaled proportionally to the target oral dose for the proposed treatment. Thus, in certain embodiments, the infusion rate can be halved to provide a sustained nimodipine dose of about 0.075 mg / hour and a bolus nimodipine dose of about 2 mg administered over about 30 minutes at about 4 hour intervals to provide an equivalent plasma exposure as an oral nimodipine capsule of 30 mg every 4 hours.

[0026] The IV nimodipine infusion regimen can be achieved by using 2 infusion pumps, one continuously running at a slow rate, and the other opening at 4-hour intervals for 30 minutes and then closing, wherein the 2 pumps deliver their infusions to a shared infusion tube by means of a three-way valve. Alternatively, a single programmable infusion pump with a preset speed can be used to deliver two infusion rates to complete the IV nimodipine infusion regimen, wherein the two infusion rates include a bolus nimodipine dose of about 4.15 mg administered in about 30 minutes, followed by a continuous nimodipine dose of about 0.15 mg / hour for 3.5 hours, (e.g., in a time period of about 21 days / 3 weeks) repeating the sequence multiple times as needed. In addition, the IV nimodipine infusion regimen can be achieved by using a single programmable infusion pump to continuously provide nimodipine at a slow rate, and the dose administered at about 4-hour intervals can be manually administered. The IV nimodipine infusion regimen can provide an effect selected from the group consisting of: (i) a more reproducible nimodipine plasma profile over the course of a day; (ii) less diurnal variation between morning and evening concentrations; (iii) less likely to be compromised by reduced or lost gastrointestinal motility or patient coma; (iv) more rapid response to dose adjustments if drug-related side effects (e.g., hypotension) occur during a course of treatment; and (v) any combination of the foregoing. In certain embodiments, the human is a patient suffering from a condition selected from aneurysm, subarachnoid hemorrhage, vasospastic angina, variant angina, stable angina, acute myocardial infarction, myocardial arrest, arrhythmia, systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery surgery, and hypertrophic cardiomyopathy.

[0027] In certain preferred embodiments, the IV nimodipine infusion regimen IV / oral ratios (%) and their corresponding 90% CIs (ranges) for the primary and secondary endpoints in human subjects completing each treatment period are Day 1 Cmax: approximately 92% (82-104); AUC Day 3 0-24hr: approximately 106% (99-114); and Day 3 Cmax: 92% (85-101).

[0028] In other embodiments, the present invention relates to providing an IV nimodipine infusion regimen in humans, which comprises administering a bolus infusion of about 3.6 mg nimodipine over about 30 minutes, followed by a continuous nimodipine infusion of about 1.2 mg / hour for up to 21 days for the treatment of subarachnoid hemorrhage. In certain embodiments, the dosing regimen provides a PK profile (e.g., Cmax and AUC 0-24 hours) equivalent to an oral 60 mg nimodipine dose.

[0029] In a further embodiment, the present invention relates to providing an IV nimodipine infusion regimen in a human, comprising administering a bolus infusion of about 4.5 mg nimodipine over about 39 minutes, followed by a continuous nimodipine infusion of about 1.2 mg / hour IV, wherein the human is a healthy volunteer. In certain embodiments, the dosing regimen provides a PK profile (e.g., Cmax and AUC 0-24 hours) equivalent to an oral 60 mg nimodipine dose.

[0030] In yet further embodiments, the present invention is directed to providing an IV nimodipine infusion regimen in humans wherein a continuous nimodipine infusion is about 0.05 mg / hour to about 1.5 mg / hour and is supplemented with (ii) a higher bolus dose of nimodipine of about 1 mg to about 8 mg administered over a period of about 20 minutes to about 50 minutes at set intervals over a 24 hour period.

[0031] The present invention also relates to a method of providing an IV nimodipine infusion regimen in a human patient comprising administering (i) a continuous nimodipine infusion at about 0.05 mg / hour to about 1.5 mg / hour over 24 hours, supplemented with (ii) a higher bolus administration of nimodipine at set intervals over 24 hours, wherein the human is a patient suffering from a condition selected from aneurysm, subarachnoid hemorrhage, vasospastic angina, variant angina, stable angina, acute myocardial infarction, myocardial arrest, arrhythmia, systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery surgery, and hypertrophic cardiomyopathy. In certain embodiments, the 24-hour AUC and Cmax of nimodipine in the IV nimodipine infusion regimen are equivalent to an oral nimodipine dose selected from 30 mg or 60 mg nimodipine administered every 4 hours. The IV nimodipine infusion regimen in a human patient is selected from the group consisting of: (i) a bolus nimodipine dose of about 4.15 mg administered over about 30 minutes, followed by a continuous nimodipine dose of about 0.15 mg / hour for 3.5 hours, repeating this sequence as many times as needed; (ii) providing a continuous nimodipine dose of about 0.075 mg / hour and a bolus nimodipine dose of about 2 mg administered over about 30 minutes at about 4 hour intervals, repeating this sequence as many times as needed; and (iii) a bolus infusion of about 3.6 mg nimodipine over about 30 minutes, followed by a continuous nimodipine infusion of about 1.2 mg / hour for up to 21 days.

[0032] As used herein, the terms "duplicate" or "mimic" or "equivalent" are synonymous with the term "similar," and they are intended to capture the concept that the IV dosing regimen of the present invention provides similar daily plasma nimodipine exposures as the oral dosing regimen of nimodipine.

[0033] As used herein, the term "unit dose" refers to physically discrete units suitable as unit doses for mammalian subjects, each unit containing a predetermined amount of nimodipine as an active ingredient. Examples of suitable unit doses of nimodipine according to the present invention include clear solutions or micelles or nanoemulsions in suitable containers (e.g., in ampule or vial).

[0034] The term "comprising" is an inclusive term and is interpreted as meaning containing, encompassing, covering or including the elements listed after the term, but not excluding other unlisted elements.

[0035] "Therapeutically effective amount" means an amount that, when administered to an animal for treating a disease, is sufficient to effectively treat the disease.

[0036] As used herein, the terms "treating" or "treatment" of a disease include preventing the disease from occurring in an animal that may be susceptible to the disease but does not yet experience or show symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side effects of the disease (including palliative care), and remitting the disease (causing regression of the disease).

[0037] By "stable" is meant that after storage at 40°C for 1 month, substantially no degradation of the concentrated intravenous infusion solution (product) is observed. In a preferred embodiment, with respect to a concentrated intravenous infusion solution comprising water-insoluble nimodipine and one or more surfactants, the term "stable" means that the degradation of nimodipine is less than about 5% (and preferably less than 4%, or less than 3%, or less than 2%, or less than 1.5%, or less than 1%), and there is no observable precipitate after storage for 48 hours; or that the nimodipine micelle structure is thermally stable during the terminal sterilization process by autoclaving at 121°C for 30 minutes, wherein the average diameter of the colloidal structure does not change by more than about 50 nanometers when comparing the colloidal structure before and after the terminal sterilization process, or both.

[0038] The term "parenteral" as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

[0039] All numbers used in the specification and claims expressing quantities of ingredients, reaction conditions, and the like are to be understood as being modified in all cases by the term "about". Therefore, unless otherwise indicated, the numerical parameters set forth in the specification and the appended claims are approximate values ​​that may vary depending on the desired properties sought to be obtained by the present invention. At the very least, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be interpreted in light of the number of significant figures and ordinary rounding techniques. DETAILED DESCRIPTION

[0040] Nimodipine is a dihydropyridine calcium antagonist. Nimodipine is isopropyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate. Its molecular weight is 418.5 and its molecular formula is C21H26N2O7. Nimodipine inhibits the transfer of calcium ions into these cells and, therefore, inhibits the contraction of vascular smooth muscle. The contractile process of smooth muscle cells depends on calcium ions, which enter these cells as a slow ionic transmembrane current during depolarization. In animal experiments, nimodipine has a greater effect on cerebral arteries than on arteries elsewhere in the body, probably because its highly lipophilic nature allows it to cross the blood-brain barrier; concentrations of up to 12.5 ng / mL of nimodipine have been detected in the cerebrospinal fluid of patients with subarachnoid hemorrhage (SAH) treated with nimodipine. The exact mechanism of action of nimodipine in humans is unknown. Although clinical studies have shown that nimodipine has a favorable effect on the severity of neurological deficits caused by cerebral vasospasm after SAH, there is no arteriographic evidence that the drug prevents or alleviates spasms in these arteries. However, it is unclear whether the arteriographic methods used are adequate to detect a clinically meaningful effect on vasospasm, if any.

[0041] Nimodipine is a pale yellow crystalline powder that is almost insoluble in water (2.5 μg / ml, 25°C). Therefore, its inherent solubility poses a challenge to the development of concentrated, stable and dilutable injectable pharmaceutical formulations. The present invention aims to solve the insufficient solubility of previously approved nimodipine dosage forms by developing a robust, stable and easy-to-administer nimodipine infusion injection. Another object of the present invention is to provide a composition and preparation of a nimodipine infusion solution and its administration.

[0042] The present invention relates in part to a regimen of replacing an oral nimodipine treatment regimen with IV nimodipine infusion to obtain equivalent daily plasma nimodipine exposure. A constant infusion of about 0.15 mg / hour of nimodipine over a 24-hour period, supplemented with 4 mg of nimodipine infused over 30 minutes at 4-hour intervals, is administered using a programmable infusion pump or using 2 infusion pumps with controllable delivery rates, which replicates the 24-hour area under the curve and 24-hour C of 60 mg nimodipine administered as an oral capsule at 4-hour intervals over a one-day course of treatment. max . Thus, 27.6 mg of IV nimodipine provides a 24-hour plasma nimodipine exposure comparable to 360 mg of oral nimodipine, and provides a similar pulsatile concentration-time curve. The IV concentration-time curve is more reproducible over the course of a day, has less diurnal variation between early morning and evening concentrations, and responds more quickly to dose adjustments if drug-related side effects (e.g., hypotension) are found during a course of treatment. In addition, IV delivery is less likely to be compromised by reduced or lost gastrointestinal motility or patient coma.

[0043] The delivery rate of IV nimodipine infusion can be adjusted proportionally to the target oral dose of the proposed treatment. For example, the infusion rate can be halved (0.075 mg / hour continuous + 2 mg in 30 minutes at 4 hour intervals) to provide an equivalent plasma exposure as 30 mg of oral nimodipine capsule every 4 hours.

[0044] IV infusion can be achieved by using 2 infusion pumps, one running continuously at a slow rate, and the other turned on for 30 minutes and then off at 4 hour intervals, with both pumps delivering their infusions into a common infusion line via a three-way valve. Alternatively, a single programmable infusion pump with preset speeds can be used to deliver both infusion rates (4.15 mg / hour for 30 minutes, followed by 0.15 mg / hour for 3.5 hours, repeating this sequence as many times as needed).

[0045] Clinical experience with this regimen has shown that the 24-hour C of nimodipine for both IV and oral routes of administration is max The values ​​were equal, and the 24-hour AUC values ​​were equal for the two routes of administration. The inter-subject variability in plasma nimodipine concentrations using the IV infusion method was approximately half of the inter-subject variability in plasma nimodipine concentrations observed after oral capsule administration. The extent of diurnal variation in plasma exposure within a one-day course of treatment using the IV dosing regimen was approximately half of the diurnal range observed for oral nimodipine administration. Liquid preparations

[0046] Two key aspects of pharmaceutically acceptable liquid formulations (e.g., for parenteral use) are the solubility of the drug in the carrier (solvent) and the stability of the final formulation (including but not limited to the ability of the formulation to prevent the drug from precipitating out of the solution). There are many examples of excipients for solubilizing poorly water soluble drugs for oral and injectable dosage forms in the prior art. Such excipients include organic solvents, surfactants, triglycerides, cyclodextrins and phospholipids. It is expected that any such formulation that provides a solubilized nimodipine IV formulation can be used in the dosing regimen of the present invention. The IV nimodipine dosing regimen can be administered as a pharmaceutical composition containing a nimodipine base or any pharmaceutically acceptable salt as an active ingredient for continuous parenteral administration. The IV nimodipine dosing regimen can be a sterile, preservative-free premix, which is used for infusion immediately without further dilution before administration. Alternatively, the IV nimodipine dosing regimen can be in the form of a concentrated injectable solution, which can be diluted in an appropriate medium (e.g., saline) to a solution for administration by infusion.

[0047] The use of organic solvents (e.g., ethanol) in parenteral formulations is limited due to the potential for precipitation of the active ingredient (drug), pain, inflammation, and hemolysis after injection. For both solubility and stability reasons, ethanol is used in existing commercially available forms of nimodipine. As previously mentioned, the nimodipine formulation currently marketed in Europe includes 23.7% ethanol.

[0048] In certain preferred embodiments, IV nimodipine formulations useful in the dosing regimens of the present invention (as compared to existing intravenous nimodipine formulations) are, for example, solutions comprising nimodipine, a hydrophilic surfactant, and a small amount of an organic solvent, wherein the nimodipine is dissolved in the small amount of the organic solvent by mixing, and the nimodipine solution is further mixed with the hydrophilic surfactant to form nimodipine micelles in a clear solution.

[0049] In further preferred embodiments, the dosing regimen (IV nimodipine treatment regimen) is a directly infusible nimodipine formulation in humans (without dilution; e.g., suitable for parenteral administration) comprising nimodipine at a concentration of from about 0.01 mg / ml to about 1.0 mg / ml, a pharmaceutically acceptable carrier (e.g., for injection), an effective amount of a hydrophilic surfactant, the pharmaceutically acceptable carrier being selected from the group consisting of aqueous solutions, organic solvents, oils, and cyclodextrins, the formulation having a volume of from about 50 ml to about 1000 ml and contained in a pharmaceutically acceptable container (e.g., a bag or vial), wherein when present, the organic solvent preferably comprises less than 2% w / v or less than 1% w / v of the formulation, the effective amount of the hydrophilic surfactant being such that the nimodipine is substantially contained in the diluted injection solution in micelles, and the formulation remains a clear solution without precipitation of nimodipine. In preferred embodiments, the hydrophilic surfactant is 0.01% to about 2.5% w / v of the directly infusible (ready-to-use) formulation. In certain embodiments, the hydrophilic surfactant is a nonionic hydrophilic surfactant, and in certain embodiments most preferably includes polysorbate 80 or consists of polysorbate 80. In certain embodiments, the organic solvent includes ethanol or consists of ethanol. In certain preferred embodiments, the pharmaceutically acceptable aqueous carrier includes water for injection. In certain preferred embodiments, the amount of the hydrophilic surfactant included is about 0.01% to about 2.5% of the directly infusible formulation. In certain preferred embodiments, the formulation is stable when exposed to conditions of 40°C ± 2°C / 75% RH ± 5% RH for at least 6 months; or when it is exposed to conditions of 25°C ± 2°C / 60% RH ± 5% RH for at least 12 months. In certain preferred embodiments, nimodipine is substantially contained within micelles as a nanoemulsion.

[0050] In other embodiments, the pharmaceutically acceptable carrier is β-cyclodextrin, wherein nimodipine is substantially contained in an inclusion complex. In certain embodiments, the unit dose of concentrate is diluted to a total volume of 5 ml with water for injection and sealed in a pharmaceutically acceptable container (e.g., an ampoule or vial). In certain preferred embodiments, the organic solvent comprises ethanol.

[0051] In embodiments of the present invention, wherein the organic solvent is contained in a pharmaceutically acceptable carrier, the organic solvent may contain, for example, at least 25% of the concentrate, and in certain embodiments, the organic solvent may contain at least 40% of the concentrate.

[0052] In certain preferred embodiments, the nimodipine concentrate has a volume of about 1 ml to about 10 ml, preferably about 5 ml, and is contained in an ampoule or vial.

[0053] In certain embodiments, the nimodipine injection concentrate is diluted to a concentration of up to 0.01 mg / ml with water for injection, saline, glucose or other commonly available infusion solutions, and it remains a clear solution and no crystalline precipitate of nimodipine is seen. The nimodipine injection concentrate can preferably be diluted with a suitable injection medium to allow, for example, administration of a single 100 ml or preferably 250 ml infusion bag or bottle, which contains, for example, less than 1% w / v alcohol in a primarily aqueous medium, and the diluted injection medium remains a clear solution without precipitating nimodipine.

[0054] The present invention also relates in part to a nimodipine formulation suitable for injection into a human body, comprising nimodipine at a concentration of about 0.01 mg / ml to about 1.0 mg / ml, a pharmaceutically acceptable carrier (e.g., for injection), an effective amount of a hydrophilic surfactant, the pharmaceutically acceptable carrier being selected from the group consisting of an aqueous solution, an organic solvent, an oil, and a cyclodextrin, the formulation occupies a volume of about 50 ml to about 1000 ml, wherein when present, the organic solvent preferably occupies less than 2% w / v of the formulation, the effective amount of the hydrophilic surfactant making the nimodipine substantially contained in the diluted injection solution, suspension, emulsion, or complex as micelles or colloidal particles or inclusion complexes, and the formulation remains a clear solution without precipitation of nimodipine. In certain embodiments, the hydrophilic surfactant is polysorbate 80. In certain embodiments, the pharmaceutically acceptable carrier is an organic solvent and also includes water for injection. In certain embodiments, the pharmaceutically acceptable carrier is an oil, and also includes about 0.005% to about 30%, more preferably about 0.5 to about 15%, and in certain embodiments includes about 0.005% to about 3.0% of a pharmaceutically acceptable hydrophilic surfactant (or emulsifier), and nimodipine is substantially contained in micelles. In certain preferred embodiments, nimodipine is substantially contained in micelles as a nanoemulsion.

[0055] In certain preferred embodiments, the emulsifier is selected from the group consisting of phospholipids and polyethylene glycol. In other embodiments, the pharmaceutically acceptable carrier is β-cyclodextrin, wherein nimodipine is substantially contained in the inclusion complex. In certain preferred embodiments, the nimodipine formulation is contained in a single infusion bag or bottle for continuous intravenous infusion. In certain preferred embodiments of the nimodipine formulation, the median particle size range of the nimodipine micelle or nanoemulsion or complex is from about 0.5 nanometers to about 350 nanometers, or from about 0.5nm to about 200nm, or from about 5nm to about 50nm. Preferably, the nimodipine formulation is clear and does not contain crystalline nimodipine precipitates. Preferably, the nimodipine formulation is stable. Preferably, the nimodipine concentrate formulation is stable. In certain preferred embodiments, nimodipine is substantially contained in micelles as a nanoemulsion. Administration of the nimodipine formulation by injection or infusion allows minimization of the first-pass metabolism of nimodipine by the liver, and compared with oral nimodipine formulations, administration of the nimodipine formulation by injection has significantly improved bioavailability. With the aid of the nimodipine injectable formulation of the present invention, consistent nimodipine levels can be maintained in the plasma and CSF of (e.g., human) patients.

[0056] In certain preferred embodiments of the above-described nimodipine concentrates and formulations, the aqueous carrier is selected from the group consisting of sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.

[0057] In certain preferred embodiments of the above-mentioned nimodipine concentrates and formulations, the oil is selected from the group consisting of fixed oils of plant origin, cottonseed oil, corn oil, sesame oil and peanut oil.

[0058] In certain preferred embodiments, the nimodipine formulation further comprises one or more preservatives. Examples of suitable preservatives include, for example, phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride, benzethonium chloride, boric acid, parabens, phenols, chlorophenolic compounds, alcohols, quarternary compounds, mercuries, and any mixture thereof.

[0059] In further embodiments, the hydrophilic surfactant comprises from about 0.01% to about 2.5% of the formulation, and in certain preferred embodiments, the hydrophilic surfactant comprises at least 0.1% of the diluted nimodipine formulation.

[0060] In certain preferred embodiments, the organic solvent comprises at least 1% of the formulation (diluted formulation).

[0061] In certain preferred embodiments, the pharmaceutically acceptable carrier comprises from about 0.1% to about 15% of the formulation.

[0062] In certain preferred embodiments, the pH of the nimodipine formulation is from about 3 to about 9, and in certain preferred embodiments, preferably from about 4.5 to about 7.5 or 8. Concentrates

[0063] One aspect of the present invention relates to the use of nimodipine injection concentrate. In such embodiments, nimodipine is mixed with a pharmaceutically acceptable carrier to prepare a concentrated injection solution, suspension, emulsion or complex. Thereafter, an effective amount of a hydrophilic surfactant is added. Optionally, a pharmaceutically acceptable medium for injection is added in a relatively small amount (e.g., 5 ml) to prepare the final nimodipine concentrated formulation.

[0064] The concentrate can be prepared by dissolving nimodipine in a small amount of an organic solvent (e.g., by mixing). Thereafter, in certain preferred embodiments, the resulting nimodipine solution is combined with an effective amount of a hydrophilic surfactant to form micelles of nimodipine in a clear solution. Thereafter, a suitable pharmaceutical medium for injection (e.g., water for injection) is added to prepare the final nimodipine concentrated formulation. In certain preferred embodiments, the organic solvent can be, for example, ethanol 95%, and the hydrophilic surfactant can be polysorbate 80. The resulting preparation includes stable micelles containing nimodipine.

[0065] The concentrate can be prepared by mixing an appropriate amount of nimodipine with an organic solvent and a hydrophilic surfactant for a sufficient period of time to form stable micelles. Thereafter, a suitable pharmaceutical medium for injection (e.g., water for injection) is added to prepare the final nimodipine concentrated formulation. In certain preferred embodiments, the organic solvent may be, for example, polyethylene glycol, and the hydrophilic surfactant may be polysorbate 80. In certain embodiments of the present invention in which an organic solvent is included, the organic solvent accounts for at least 25% (and in certain embodiments at least 40%) of the preparation in the injection concentrate, and is at least 1% in the final diluted injection solution. In other preferred embodiments, the solvent accounts for about 10 to about 90% by weight in the injection concentrate, and is preferably greater than 30% to about 90%, and is about 0.1 to about 4% in the final diluted injection solution.

[0066] In certain preferred embodiments, the nimodipine injection concentrate formulation comprises: nimodipine at a concentration of about 0.5 mg / ml to about 5 mg / ml; an organic solvent in an amount greater than 30% to about 90%, w / w; about 0.005 to about 30%, preferably about 0.5% or 1% to about 15% of a hydrophilic surfactant; and a pharmaceutically acceptable aqueous carrier for injection, which accounts for about 30% to about 80% of the concentrated formulation, so that the nimodipine in the concentrate is contained in micelles. In preferred embodiments, the formulation is stable and clear. In certain embodiments, the hydrophilic surfactant is polysorbate 80. In certain embodiments, the pharmaceutically acceptable carrier is water for injection, and nimodipine is substantially contained in micelles. In certain preferred embodiments, the organic solvent comprises ethanol or consists of ethanol. In certain embodiments, the unit dose of the concentrate is diluted with water for injection to a total volume of 5 ml and is enclosed in a pharmaceutically acceptable container (e.g., an ampoule or vial). In certain embodiments, the nimodipine injection concentrate also includes an effective amount of a preservative. In certain preferred embodiments of the nimodipine injection concentrate, the median particle size of the micelle or nanoemulsion ranges from about 0.5 nanometers to about 350 nanometers, or from about 0.5 nm to about 200 nm, or from about 5 nm to about 50 nm. Preferably, the nimodipine concentrate is clear and does not contain crystalline nimodipine precipitates. In certain preferred embodiments, nimodipine is substantially contained in micelles as a nanoemulsion. The nimodipine concentrated formulation (e.g., as described above) can be diluted in a suitable injection medium so that the diluted formulation for injection contains less than about 2% or preferably less than about 1% w / v of an organic solvent (e.g., alcohol). The solution is preferably primarily an aqueous medium, and the diluted injection medium remains a clear solution in which no nimodipine precipitation is seen. When the concentrate is diluted in a suitable injection medium, a single 250 ml infusion bag or bottle is allowed to be administered parenterally to a human patient, and the diluted formulation contains less than about 2% or preferably less than about 1% w / v of an organic solvent (e.g., alcohol). In certain embodiments, the concentrate and diluted solution further comprise an effective amount of a pharmaceutically acceptable preservative. In certain preferred embodiments, substantially all or all of the nimodipine contained in the formulation is contained in micelles.

[0067] In other embodiments, nimodipine at a concentration of about 0.5 mg / ml to about 5 mg / ml, about 1% to about 15% of a hydrophilic surfactant, and about 10% to about 90% of a pharmaceutically acceptable carrier for injection of the formulation injection concentrate, the pharmaceutically acceptable carrier for injection being selected from the group consisting of an aqueous solution, an organic solvent, an oil, and a cyclodextrin, such that nimodipine is substantially contained in a concentrated injection solution, suspension, emulsion, or complex as micelles or colloidal particles or inclusion complexes, and the formulation is stable and clear. In certain embodiments, the hydrophilic surfactant is polysorbate 80. In certain embodiments, the pharmaceutically acceptable carrier is water for injection, and also includes about 0.5% to about 30% of a pharmaceutically acceptable hydrophilic surfactant (or referred to herein as an emulsifier), and nimodipine is substantially contained in micelles. In other embodiments, the pharmaceutically acceptable carrier is an organic solvent, and the concentrate also includes water for injection. In other embodiments, the pharmaceutically acceptable carrier is an oil, and also includes about 0.005% to about 30%, more preferably about 0.5 to about 15% of a pharmaceutically acceptable hydrophilic surfactant, and nimodipine is substantially contained in micelles. In certain preferred embodiments, the hydrophilic surfactant (emulsifier) ​​is selected from the group consisting of phospholipids and polyethylene glycol. In certain embodiments, the unit dose of concentrate is diluted to a total volume of 5 ml with water for injection and is enclosed in a pharmaceutically acceptable container (e.g., an ampoule or a vial). In certain embodiments, the nimodipine injection concentrate also includes an effective amount of a preservative. In certain preferred embodiments of the nimodipine injection concentrate, the median particle size range of the micelle or nanoemulsion is about 0.5 nanometers to about 350 nanometers, or about 0.5nm to about 200nm, or about 5nm to about 50nm. Preferably, the nimodipine concentrate is clear and does not contain crystalline nimodipine precipitates. Preferably, the nimodipine concentrate formulation is stable. In certain preferred embodiments, nimodipine is substantially contained within micelles, as a nanoemulsion.

[0068] The concentrate can be prepared by mixing an appropriate amount of nimodipine with a pharmaceutically acceptable oil carrier and a hydrophilic surfactant until a clear solution is obtained, and adding at least one pharmaceutically acceptable emulsifier to prepare a nanoemulsion and / or a self-emulsifying concentrated formulation. The self-emulsifying formulation will form a nanoemulsion once diluted with water for injection or any commonly used intravenous infusion solution. In these embodiments, preferably, nimodipine is in an oil phase (preferably soybean oil, medium-chain glycerides, oleic acid, ethyl oleate) and other pharmaceutically acceptable excipients alone or in combination with an emulsifier and water for injection. In certain embodiments, the emulsifier can be, for example, phospholipids Lipoid 80 and / or PEG 400. The median particle size range of the micelle or nanoemulsion is from about 0.5 nanometers to about 350 nanometers. In certain embodiments of the present invention in which an oil carrier is included, the oil carrier accounts for about 1% to about 30% of the formulation in the injection concentrate, and is about 0.005% to about 3% in the final diluted injection solution. In other preferred embodiments, the oil in the injection concentrate accounts for about 5% to about 20% of the formulation by weight, and is about 0.025% to about 2% in the final diluted injection solution. The amount of the emulsifier can account for about 1% to about 30% of the formulation in the injection concentrate, and is about 0.005% to about 3% of the final diluted injection solution.

[0069] In other embodiments, the present invention relates to a method for preparing a nimodipine formulation (concentrate) for intravenous administration, comprising mixing nimodipine at a concentration of about 0.5 mg / ml to about 5 mg / ml with a pharmaceutically acceptable carrier, so that the pharmaceutically acceptable carrier for injection accounts for about 10% to about 90% of the concentrate; thereafter, adding about 1% to about 15% of a hydrophilic surfactant to prepare a concentrated injection solution, suspension, emulsion or complex; and optionally adding about 0.5 ml to about 4.0 ml of a pharmaceutically acceptable medium for injection to prepare a nimodipine concentrated formulation. Preferably, the nimodipine concentrate is clear and does not contain crystalline nimodipine precipitates. The method may also include diluting the nimodipine concentrate in a pharmaceutically acceptable carrier for injection to a volume of about 50 ml to about 1000 ml, wherein the pharmaceutically acceptable carrier for injection is selected from the group consisting of aqueous solutions, organic solvents, oils and cyclodextrins, wherein when present, the organic solvent accounts for less than 2% w / v of the formulation, and the formulation remains a clear solution and no crystalline precipitate of nimodipine is seen. In certain preferred embodiments of the nimodipine concentrate or diluted formulation, the median particle size of the nimodipine micelle or nanoemulsion or complex ranges from about 0.5 nm to about 350 nm, or from about 0.5 nm to about 200 nm, or from about 5 nm to about 50 nm.

[0070] The nimodipine infusion rate can be, for example, about 0.05 mg nimodipine per hour to about 5 mg nimodipine per hour. In certain embodiments, the intravenous nimodipine dose is about 2 to 10 mg every five hours. In certain embodiments, the nimodipine formulation is administered by intravenous push, intravenous infusion, intraarterial, oral, or intranasal using a nasogastric tube. In certain embodiments, the method further comprises diluting to 2.5 x 10 -5 molar nimodipine solution to flush the exposed artery after clipping the aneurysm and before administering intravenous nimodipine to improve patient outcomes.

[0071] In another embodiment of the present invention, an appropriate amount of nimodipine and a hydrophilic surfactant are mixed together in an appropriate amount of cyclodextrin (e.g., β-cyclodextrin) in water for a sufficient period of time to form a stable nimodipine inclusion complex. In such an embodiment, the cyclodextrin preferably accounts for about 5% to about 45% of the formulation in the injection concentrate, and is about 0.025% to about 4.5% of the final diluted injection solution.

[0072] In certain embodiments of the present invention, the hydrophilic surfactant comprises at least about 8% of the formulation in the injection concentrate and at least 0.1% in the final diluted injection solution. In other preferred embodiments, the hydrophilic surfactant comprises about 1% to about 15% of the formulation by weight of the injection concentrate and about 0.01% to about 2.5% of the final diluted injection solution.

[0073] In certain preferred embodiments, the hydrophilic surfactant includes a pharmaceutically acceptable nonionic surfactant. Preferably, the amount of the nonionic surfactant included is sufficient to inhibit the precipitation of the drug from a pharmaceutically acceptable medium (e.g., an aqueous solution) for injection after dilution. The nonionic surfactant forms stable micelles with the drug substance, which can solubilize the drug and may impart additional light stability to the drug.

[0074] Using the HLB value as a rough guide, hydrophilic surfactants are considered to be those compounds having an HLB value greater than 10, particularly HLB values ​​of 12 to 17. Hydrophilic nonionic surfactants are more soluble in water than in oil (having an HLB above 10).

[0075] Pharmaceutically acceptable nonionic surfactants that can be used for the preparation of the present invention include, but are not limited to, for example, polyoxyethylene compounds, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols, ethoxylated / propoxylated block polymers, and propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glycerides, polyglycerol fatty acid esters, sorbitol esters, sucrose esters, and glucose (dextrose) esters. Other examples are the reaction products of natural or polyethoxylated castor oil and ethylene oxide. The ethylene oxide content of ethoxylated castor oil can be 25 to 100 moles of ethylene oxide per molecule, preferably 35 to 60 moles of ethylene oxide per molecule. Natural or polyethoxylated castor oil can react with ethylene oxide in a molar ratio of about 1:35 to about 1:60, optionally removing polyethoxylated components from the product. Nonionic hydrophilic surfactants that can be used in the present invention also include alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauroyl polyoxyethylene glycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol (mono and di) fatty acid esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols and the like; polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils; a reaction mixture of a polyol and at least one member selected from the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, sterols; sugar esters, sugar ethers; sucrose glycerides; fatty acid salts, bile salts, phospholipids, phosphates, carboxylates, sulfates, sulfonates. More specifically, the nonionic surfactant may include, for example, polyoxyethylene fatty alcohol esters, sorbitan fatty acid esters (Spans), polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene (20) sorbitan monooleate (Tween 80), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan monolaurate (Tween 20) and other Tweens), sorbitan esters, glycerides, for example, Myrj and triacetin, polyethylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, polysorbate 80, poloxamers, poloxamines, polyoxyethylene castor oil derivatives (e.g., RH40, Cremphor A25, Cremphor A20, EL) and other polyoxyethylene hydrogenated castor oils (Cremophors), sulfosuccinates, alkyl sulfates (SLS); PEG glyceryl fatty acid esters, such as PEG-8 glyceryl caprylate / caprate (Labrasol), PEG-4 glyceryl caprylate / caprate (Labrafac Hydro WL1219), PEG-32 glyceryl laurate (Gelucire 444 / 14), PEG-6 glyceryl monooleate (Labrafil M1944CS), PEG-6 glyceryl linoleate (Labrafil M 2125CS); propylene glycol mono- and di-fatty acid esters, such as propylene glycol laurate, propylene glycol caprylate / caprate; 700, ascorbic acid-6-palmitate, stearylamine, sodium lauryl sulfate, polyoxethyleneglyceroltriiricinoleate, and any combination or mixture thereof. Although polyethylene glycol (PEG) itself does not act as a surfactant, various PEG-fatty acid esters have useful surfactant properties. Among the PEG-fatty acid monoesters, esters of lauric acid, oleic acid, and stearic acid are the most useful.

[0076] The examples thereof include PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and PEG-20 oleate. Polyethylene glycol fatty acid esters are also suitable for use as surfactants in the compositions of the present invention, such as PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate and PEG-30 glyceryl oleate. The hydrophilic surfactant can also include any mixture of the above.

[0077] Polysorbate 80 is a particularly preferred hydrophilic nonionic surfactant in the preparation of the present invention. It is a commonly used surfactant in protein parenteral preparations for minimizing denaturation at the air-water interface. Polysorbate 80 is sometimes also used in injectable solution preparations of small molecules for the purpose of solubility enhancement due to micelle formation. Polysorbates are nonionic surfactants of sorbitan esters. Polysorbates that can be used in the present invention include, but are not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (Tween 80) and any combination or mixture thereof. Other suitable preferred surfactants include poloxamer, poloxamer 407, transcutol. The surfactant can be any surfactant suitable for use in a pharmaceutical composition. Suitable surfactants can also be ionic hydrophilic surfactants or hydrophobic surfactants. Although nonionic hydrophilic surfactants are currently preferred, suitable hydrophilic surfactants can be anionic, cationic, zwitterionic or nonionic. Preferably, the nimodipine preparation of the present invention includes at least one nonionic hydrophilic surfactant.

[0078] However, in other embodiments, the nimodipine formulation may include a mixture of two or more nonionic hydrophilic surfactants, as well as a mixture comprising at least one nonionic hydrophilic surfactant and at least one hydrophobic surfactant.

[0079] In certain embodiments, the surfactant may be one or more of the surfactants described in US Pat. No. 6,363,471.

[0080] In certain embodiments of the invention, the organic solvent is an alcohol (eg, ethanol) and the solubilizing agent is a polysorbate.

[0081] In the above examples, a surfactant is used as a solubilizing agent to solubilize nimodipine by forming colloidal particles called micelles, and nimodipine is stabilized by using a cosolvent and / or an appropriate matrix in an aqueous formulation. This results in the formation of micelles or tiny colloidal particles that surround the nimodipine molecule, isolating it from the water molecules surrounding it, and forming a clear aqueous solution. The liquid formulation is suitable for parenteral, nasal or oral administration.

[0082] Water-miscible surfactant molecules (such as polysorbates) are composed of two parts, hydrophobic and hydrophilic, which can solubilize selected water-insoluble drugs. Once the concentration of surfactant monomers reaches the critical micelle concentration, the surfactant can also self-assemble to form micelles. Therefore, surfactants can solubilize drug molecules either by direct cosolvent action or by absorption into micelles. Commercially available nonionic surfactants in soluble oral and injectable formulations include Cremophor EL, Cremophor RH 40, polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), d-tocopheryl polyethylene glycol 1000 succinate (TPGS), Solutol HS-15, Sorbitan monooleate (Span 80), polyoxyl 40 stearate, and various polyglycolyzed glycerides, including Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, and Softigen 767.

[0083] In the present invention, the nimodipine formulation preferably forms a colloidal structure (micelle) with a diameter of about 10 nm. In other preferred embodiments, the average diameter of the colloidal structure varies from 0.5 nm to about 200 nm, and more preferably from about 5 nm to about 50 nm. In the present invention, the nimodipine micellar structure is thermally stable during the final sterilization process by autoclaving at 121° C. for 30 minutes.

[0084] In embodiments where an oil carrier is used, the formulation may include an oil carrier, for example, in the form of a commercially available emulsion, including Intralipid (10-20% soybean oil), Liposyn (10-20% safflower oil), and Lipofundid MCT / TCL (5-10% soybean oil and medium chain triglycerides). Nimodipine is oil soluble, and because nimodipine partitions into the oil phase, it can be formulated in an oil-in-water emulsion for intravenous administration.

[0085] In certain preferred embodiments, the nimodipine injectable formulation is a cyclodextrin inclusion complex. Suitable cyclodextrins include, but are not limited to, β-cyclodextrins, such as hydroxy-propyl-β-cyclodextrin and β-cyclodextrins including one or more hydroxybutylsulfonic acid moieties, such as sulfobutyl-ether-β-cyclodextrin, α-cyclodextrin, γ-cyclodextrin, and cyclodextrins described in U.S. Pat. No. 6,610,671 or U.S. Pat. No. 6,566,347. In one embodiment, the nimodipine injectable formulation includes a β-cyclodextrin inclusion complex, which is formed by mixing nimodipine, a hydrophilic surfactant, and β-cyclodextrin for 48 to 78 hours, and occasionally heating in a water bath at a temperature of about 60 degrees to increase complex formation.

[0086] The present invention may use any suitable pharmaceutically acceptable water-miscible organic solvent. The selection of a suitable organic solvent will depend in part on the solubility of the active substance (nimodipine) in the solvent, the degree to which the solvent is miscible in water, and the tolerance of the solvent. The solvent should be physiologically acceptable. Examples of solvents that can be used in the present invention include, but are not limited to, various alcohols, such as ethanol, glycol, glycerol, propylene glycol, and various polyethylene glycols and dimethyl isosorbide (DMI). Other alcohols that can be used include, but are not limited to, methanol (methanol / methyl alcohol), ethanol (ethanol / ethyl alcohol), 1-propanol (n-propanol), 2-propanol (isopropanol), 1-butanol (n-butanol), 2-butanol (sec-butanol), 2-methyl-1-propanol (isobutanol), 2-methyl-2-propanol (tert-butanol), 1-pentanol (n-pentanol), 3-methyl-1-butanol (isopentanol), 2,2-dimethyl-1-propanol (neopentyl alcohol), cyclopentanol (cyclopentyl alcohol), 1-hexanol (n-hexanol), cyclohexanol (cyclohexanol), 1-heptanol (n-heptanol), 1-octanol (n-octanol), 1-nonanol (n-nonanol), 1-decanol (n-decanol), 2-propylene- 1-propenyl alcohol (propylene alcohol), benzyl alcohol (benzyl alcohol), benzhydrol (diphenylmethanol), triphenylmethanol (triphenylmethanol), glycerol, phenol, 2-methoxyethanol, 2-ethoxyethanol, 3-ethoxy-1,2-propanediol, di(ethylene glycol) methyl ether, 1,2-propanediol, 1,3-propanediol, 1,3-butanediol, 2,3-butanediol, 1,4-butanediol, 1,2-pentanediol, 1,3-pentanediol, 1,4-pentanediol, 1,5-pentanediol, 2,3-pentanediol, 2,4-pentanediol, 2,5-pentanediol, 3,4-pentanediol and 3,5-pentanediol.

[0087] In embodiments where an emulsifier is incorporated into the concentrate, the emulsifier may be a pharmaceutically acceptable polyethylene glycol. Polyethylene glycol has many different grades with various molecular weights. For example, the polyethylene glycol may be PEG 200; PEG 300; PEG 400; PEG 540 (blended); PEG 600; PEG 900; PEG 1000; PEG 1450; PEG 1540; PEG 2000; PEG 3000; PEG 3350; PEG 4000; PEG 4600 and PEG 8000. In certain embodiments, the polyethylene glycol used to prepare the nimodipine concentrate is preferably PEG 400.

[0088] The nimodipine concentrate of the present invention may be contained in unit doses in any pharmaceutically acceptable container (eg, ampoule, vial) for subsequent dilution (eg, at the place and time of administration to a human patient). dilution

[0089] The injectable nimodipine formulation of the present invention is preferably clear and contains nimodipine in micelles or inclusion compounds, etc., which can be diluted with a pharmaceutically acceptable carrier for injection (e.g., water for injection) to produce a thermodynamically stable dispersion of non-ionic surfactant nanoparticles (which are micelles, inclusion compounds, etc.) as described and disclosed herein. The diluted nimodipine formulation is stable, that is, nimodipine will not separate across a wide range of temperatures, a wide range of water hardness, and a wide range of pH values. Therefore, the nimodipine injection concentrate disclosed herein, when used with water for injection, saline, glucose or a commonly used infusion solution. In certain embodiments, the concentration of the diluted nimodipine formulation is about 0.05 mg / ml to about 0.2 mg / ml. For example, the concentration of the diluted nimodipine formulation can be 0.08 mg / ml, 0.12 mg / ml, 0.16 mg / ml or 0.2 mg / ml. In certain preferred embodiments, the concentration of the diluted nimodipine formulation remains a clear solution and no precipitation of nimodipine is observed.

[0090] According to the present invention, the nimodipine formulation allows for administration of a single 250 ml infusion bag or bottle containing IV nimodipine in a primarily aqueous medium, which is a significant improvement over IV nimotop. In certain embodiments, the solution may contain a low alcohol content. For example, the alcohol content of the nimodipine formulation may be, for example, about 0% to about 5%. In certain preferred embodiments, the nimodipine formulation may contain less than 2% or less than 1% w / v alcohol. The lower alcohol content in this formulation provides many advantages known to those skilled in the art, for example, making the nimodipine formulation of the present invention suitable for administration to patients suffering from alcoholism or impaired alcohol metabolism and those pregnant or lactating women.

[0091] The present invention is a micellar formulation of nimodipine that provides greatly enhanced water solubility and stability (including photostability). Nimodipine does not precipitate from the formulation even when the formulation is diluted with water to 250 times its initial concentration.

[0092] In certain embodiments of the present invention, the nimodipine injection concentrate is diluted in an infusion bag containing water for injection or any commonly used intravenous infusion solution. The infusion volume can range from about 50 ml to about 1000 ml. The present invention provides a preparation diluted in a single infusion bag and infused over a specific period of time, unlike Bayer's nimotong intravenous injection, which requires a three-way valve to assist in infusing the nimotong solution with the other two co-infusion solutions to prevent any drug precipitation. The present invention provides a single infusion solution that will not precipitate during dilution and / or administration, thereby improving safety and effectiveness.

[0093] In certain preferred embodiments, the nimodipine injection can be further diluted to 2.5 x 10 -5 molar nimodipine solution to flush exposed arteries after aneurysm clipping and before administration of intravenous nimodipine to improve patient outcomes.

[0094] In certain preferred embodiments, the novel solvent-free (eg, less than 1% w / v organic solvent, such as ethanol) nimodipine formulations can be administered by intravenous bolus, intravenous infusion, intra-arterially, intra-orally, or intranasally using a nasogastric tube.

[0095] In certain preferred embodiments, after diluting the nimodipine injection with a common infusion solution, the infusion set and bag may be covered with an ultraviolet (UV) protective bag to further protect them from light degradation.

[0096] The compounds of the present invention can be administered parenterally as required in the form of a preparation that finally contains conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.

[0097] Injectable preparations (e.g., sterile injectable aqueous or oily suspensions) can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents. Among acceptable vehicles and solvents are water, Ringer's solution, and isotonic sodium chloride. In addition, sterile fixed oils are generally used as solvents or suspension media. For this purpose, any gentle (bland) fixed oils can be used, including synthetic monoglycerides or diglycerides, and in addition, fatty acids (e.g., oleic acid) can also be applied to the preparation of injections. Suitable carriers for intravenous administration include physiological saline or phosphate buffered saline (PBS) and solutions containing solubilizers, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.

[0098] The preparation may include an aqueous vehicle. Aqueous vehicles include, but are not limited to, sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water injection, glucose and lactated Ringer's injection. Non-aqueous parenteral vehicles include, but are not limited to, fixed oils of plant origin, cottonseed oil, corn oil, sesame oil and peanut oil.

[0099] Antimicrobial agents at bacteriostatic or fungistatic concentrations must be added to parenteral formulations packaged in multidose containers, including phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride, benzethonium chloride, boric acid, parabens, phenols, chlorophenolic compounds, alcohols, quaternary compounds, mercurials, and mixtures thereof, etc. For example, isotonic agents include, but are not limited to, sodium chloride and glucose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinyl pyrrolidone. Emulsifiers include polysorbate 80 ( 80) [Sealants or chelators for metal ions, including EDTA.] For example, pharmaceutically acceptable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid or lactic acid. The nimodipine formulations of the present invention may additionally include physiologically acceptable components, such as sodium chloride and similar substances that are commonly used to achieve isotonicity with typical body fluids, pH buffers for establishing a physiologically compatible pH range and improving the solubility of nimodipine, preservatives, stabilizers and antioxidants, and the like.

[0100] In certain preferred embodiments, the injectable preparations after dilution with water for injection and other commonly used intravenous infusion solutions, the pH value of the final diluted solution will be about 3 to about 9, and in certain preferred embodiments, about 4.5 to about 8. In some embodiments of the present invention, a pharmaceutically acceptable buffer or alkalizing agent is used to adjust the pH value, and suitable alkalizing agents and buffers include but are not limited to NaOH, KOH, triethylamine, meglumine, L-arginine, sodium phosphate buffer (trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate or o-phosphoric acid), sodium bicarbonate, and any mixture thereof.

[0101] In certain other embodiments, the formulation is made isotonic by adding a tonicity agent, such as, but not limited to, any pharmaceutically acceptable sugar, salt, or any combination or mixture thereof, such as, but not limited to, glucose and sodium chloride. The tonicity agent may be present in an amount of about 100 mOsm / kg to about 500 mOsm / kg, or about 200 mOsm / kg to about 400 mOsm / kg, or about 280 mOsm / kg to about 320 mOsm / kg. Nimodipine stability

[0102] Drug stability refers to the ability of the IV nimodipine formulations that can be used in the present invention to maintain the physical, chemical, therapeutic and microbiological properties of nimodipine during storage and use in patients. It is measured by the rate of change that occurs in the drug dosage form. According to the guidelines established by ICH, drug doses cannot be used after the levels of known and unknown impurities exceed the limits. In addition, some drug degradation products are toxic and harmful to patients. There are several factors that affect drug stability; among them, oxidative degradation is a major factor. This oxidative degradation rate is proportional to the amount of oxygen available to the drug in the formulation. Temperature increases oxidative degradation. Our experimental studies clearly show that headspace oxygen (overhead oxygen) and dissolved oxygen play an important role in the stability of nimodipine IV formulations. Degassed injection water used for formulation preparation and inert gas coverage (purging with inert gas) during processing and filling provide a robust and stable nimodipine IV drug formulation. In order to obtain a more stable drug formulation, the dissolved oxygen content in the nimodipine formulation should be about 2.0 ppm, and the headspace oxygen content should be less than 5%. After dilution as described above, the nimodipine formulations of the present invention are preferably chemically stable for up to at least 48 hours for continuous infusion. Treatment with nimodipine

[0103] According to the present invention, intravenous nimodipine solution can treat conditions such as, but not limited to, aneurysm, subarachnoid hemorrhage, vasospastic angina, variant angina, stable angina, acute myocardial infarction, myocardial arrest, arrhythmia, systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery surgery, and hypertrophic cardiomyopathy.

[0104] Nimodipine is indicated for the treatment of ischemic neurological deficits following aneurysmal subarachnoid hemorrhage. 0.02% solution for infusion (Bayer plc), the recommended treatment is as follows: For the first two hours of treatment, 1 mg of nimodipine, i.e. 5 ml of nimotong solution (about 15 μg / kg bw / h) should be infused every hour through a central venous catheter. If well tolerated, the dose should be increased to 2 mg of nimodipine per hour, i.e. 10 ml of nimotong solution (about 30 μg / kg bw / h) after two hours, provided that no severe drop in blood pressure is observed. Patients weighing less than 70 kg or with unstable blood pressure should start with a dose of 0.5 mg of nimodipine (2.5 ml of nimotong solution) per hour, or less if necessary. Nimotong capsules are also available in the United States for oral administration, each capsule containing 30 mg of nimodipine, with glycerin, peppermint oil, purified water and polyethylene glycol 400 as the vehicle. The oral dose is 60 mg (2 tablets, 30 mg each) every 4 hours for 21 consecutive days, preferably not less than one hour before or two hours after a meal.

[0105] In certain embodiments of the present invention, IV nimodipine solution can be continuously infused over a period of about 3 weeks. The infusion rate can be adjusted based on the patient's tolerance and to avoid a drop in blood pressure. The preferred infusion rate is about 0.05 mg nimodipine per hour to about 5 mg nimodipine per hour. The oral dosage form currently approved by the U.S. FDA cannot be adjusted in dosage.

[0106] In certain embodiments of the present invention, compared with the currently approved oral dose of 60 mg every four hours, the IV nimodipine dose is reduced to 2 to 10 mg every five hours, without reducing the effectiveness and safety of the drug product. The oral nimodipine drug product currently approved by the U.S. FDA has a high first-pass metabolism and produces a large number of metabolites, which are inactive or much less active than the parent compound. After oral administration, the bioavailability of nimodipine is 13% on average. First-pass metabolism is avoided by intravenous administration, and the variability in the subject (patient) body associated with the currently approved oral dosage form is reduced. In addition, the single bag and or bottle of nimodipine preparation of the present invention is a convenient method for administering effective concentrations of nimodipine to unconscious patients and patients who have difficulty swallowing oral dosage forms. Detailed Description of the Preferred Embodiments

[0107] The following examples of formulations according to the present invention should not be construed as limiting the invention in any way, but are merely samples of the various formulations described herein. Example 1-4

[0108] The formulations of Examples 1-4 are prepared as follows: nimodipine is added to ethanol while stirring and mixing until a clear solution is observed. Polysorbate 80 is then added as a surfactant while stirring and mixing for 30 minutes to form stable micelles. The volume is then increased to 5 ml with water for injection to prepare a nimodipine injection concentrate formulation. The nimodipine injection concentrate can be diluted with any amount of common intravenous infusion solution. The ingredients of Examples 1-4 are listed in Table 1 below: Table 1 Example 5

[0109] The nimodipine formulation of Example 3 was tested in a dilution study with different commonly used intravenous infusion solutions (0.9% sodium chloride, 5% glucose and lactated Ringer's solution) to understand chemical interactions and observe whether nimodipine crystals were precipitated after dilution. As shown in Table 2 below, no nimodipine crystals were observed after diluting this formulation with these three different IV infusion solutions. Table 2

[0110] Figure 1 is a graphical representation of the nimodipine concentration of the formulation of Example 3 at the tested concentrations (0.2 mg / ml, 0.02 mg / ml and 0.01 mg / ml) in 0.9% sodium chloride solution.

[0111] Figure 2 is a graphical representation of the nimodipine concentration of the formulation of Example 3 at the tested concentrations (0.2 mg / ml, 0.02 mg / ml and 0.01 mg / ml) in 5% glucose solution.

[0112] Figure 3 is a graphical representation of the nimodipine concentration of the formulation of Example 3 at the tested concentrations (0.2 mg / ml, 0.02 mg / ml and 0.01 mg / ml) in Lactated Ringer's solution.

[0113] The concentrated formulation of Example 3 was also exposed to UV light for 48 hours under a controlled UV chamber to understand the photodegradation of this new nimodipine formulation. The nimodipine formulation was stored in amber and clear glass vials under the same conditions. As shown in Table 3 below, no photodegradation was observed in both the amber and clear glass vials. This result supports the conclusion that the concentrate (micelle) formulation of Example 3 provides photostability for nimodipine. # Table 3

[0114] Figure 4 is a graphical representation of the duration of UV light exposure of the nimodipine formulation of Example 3, wherein the formulation has a nimodipine concentration of 2 mg / ml and is contained in an amber vial and a clear glass vial. The graph shows the change in nimodipine concentration over time. Example 6-8

[0115] In Example 6-8, the nimodipine concentrate is prepared as follows: nimodipine is added to polysorbate 80 and polyethylene glycol 400, stirred and mixed for 30 minutes to form stable micelles, and the volume is made up to 5 ml with water for injection. Benzyl alcohol is added as a preservative. This nimodipine injection concentrate can be diluted with any amount of common intravenous infusion solution. The formulations of Examples 6-8 are listed in more detail in Table 4 below: Table 4 Example 9-11

[0116] In Examples 9-11, the nimodipine concentrate is prepared as follows: nimodipine is added to polysorbate 80 and soybean oil, while stirring and mixing until a clear solution is observed, and phospholipid 80 and PEG400 are used as emulsifiers to prepare a nanoemulsion and / or a self-emulsifying formulation. This nimodipine injection concentrate can be diluted with any amount of a common intravenous infusion solution to form a nanoemulsion. The formulations of Examples 9-11 are listed in more detail in Table 5 below: Table 5 Example 12

[0117] In Example 12, nimodipine concentrate was prepared as follows: β-cyclodextrin was added to water for injection while stirring and mixing for 15 minutes, and nimodipine and polysorbate 80 were added while stirring the above dispersion and mixing for 48 hours to obtain a clear solution. Heating was performed using a water bath heated to 60 degrees to increase the rate of inclusion. The formulation of Example 12 is listed in more detail in Table 6 below: Table 6 Example 13

[0118] In Example 13, the nimodipine concentrate of Example 3 was subjected to a terminal sterilization process by autoclaving at 121° C. for 30 minutes. Figure 5 is a graph showing the micelle size distribution of Example 3 before terminal sterilization, with a peak at a particle size diameter of about 10 nm. The size distribution was measured using a Malvern Zetasizer Nano ZS at a temperature of 25°C. Figure 6 is a graph showing the micelle size distribution of Example 3 after terminal sterilization (autoclaving at 121° C. for 30 minutes) with a peak at a particle size diameter of about 10 nm. The size distribution was measured using a Malvern Zetasizer Nano ZS at a temperature of 25° C. Based on these results, the formulation of Example 3 is considered stable. Example 14

[0119] The formulation of Example 14 is prepared as follows: nimodipine is added to ethanol while stirring and mixing until a clear solution is observed. Polysorbate 80 is then added as a surfactant while stirring and mixing for 30 minutes to form stable micelles. Sufficient water for injection is then added to the solution to produce 5 ml of nimodipine injection concentrate. The nimodipine injection concentrate can be further diluted with any amount of common intravenous infusion solution. The ingredients of Example 14 are listed in Table 7 below: Table 7 Example 15 (Stability)

[0120] Amber glass bottles with rubber stoppers and flip-off seals were filled with the formulations of Example 3 (5 mL concentrate), Example 3 (100 mL ready to infuse), and Example 14 (5 mL concentrate) and subjected to stability studies under the following conditions: -ICH accelerated conditions at 40°C ± 2°C / 75% RH ± 5% RH; and -ICH room temperature conditions are 25℃±2℃ / 60%RH±5%RH.

[0121] The samples were analyzed to measure nimodipine content, impurities. The physical stability of the invented formulations, such as physical appearance and pH changes, was also recorded. The stability of the concentrate of Example 3 is provided in Table 8 below. Table 8: Stability data of Example 3 concentrate (5 ml amber vial) ND Not detected; Y – consistent The stability of the immediate infusion embodiment of Example 3 is provided in Table 9 below. Table 9: Stability data of Example 3 immediate infusion type (100 ml amber vial) ND Not detected; Y – consistent The stability of the concentrate of Example 14 is provided in Table 10 below: Table 10: Stability data of Example 14 concentrate (5 ml amber vial) ND Not detected; Y – consistent Example 16 (In vivo study)

[0122] In vivo studies were conducted in healthy Wistar rats to evaluate the drug release from the nimodipine continuous intravenous infusion prepared according to Example 14. A single dose parallel study was conducted to evaluate the plasma and CSF (cerebrospinal fluid) pharmacokinetics and relative bioavailability of a single intravenous infusion of 0.73 mg nimodipine (lasting 4 hours) and a 5.5 mg nimodipine oral solution (Nymalize). Pharmacokinetic studies were conducted on 6 healthy rats (3 males and 3 females). The test formulation was a single 0.73 mg dose of nimodipine (with a concentration of 0.182 mg / ml after dilution with a 5% glucose aqueous solution (D5W) infusion solution), administered as a continuous intravenous infusion at a controlled rate over a 4-hour period (continuous infusion). The reference product was nimodipine 5.5 mg oral solution Nymalize (the oral bioavailability of nimodipine was an average of 13%, and the oral dose was adjusted accordingly), which was orally administered with the help of oral gavage. Blood samples were collected at 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 12, and 24 hours after dosing. CSF samples were collected at 1, 2, 4, and 24 hours after dosing. All samples were analyzed using a validated LC-MS analytical method. Table 11

[0123] After a single dose of 0.73 mg administered by continuous infusion over 4 hours, the median T max The average C at 1.92 hr max The average AUC was 249 ng / mL.0-t and AUC 0-无穷 The mean elimination half-life was found to be 3.68 hr. The clearance and volume of distribution were 11.4 mL / min and 3.66 L, respectively.

[0124] After administration of a single 5.5 mg oral solution dose, the median T max The mean Cmax at 0.75 hr was 479 ng / mL. 0-t and AUC 0-无穷 1850 and 1850 ng*hr / mL respectively. The mean elimination half-life was found to be 2.6 hr. The relative bioavailability was found to be 22.6% relative to continuous intravenous infusion of the test product.

[0125] In Table 12, Table 13 and Figure 7 The pharmacokinetic results are reported in [Mean plasma concentration-time profiles of nimodipine in rats following continuous intravenous infusion of the reference (oral solution) and the test product (Example 14)]. Table 12: Pharmacokinetic results of nimodipine continuous infusion Table 13: Pharmacokinetic results of nimodipine oral solution Table 14: Plasma and CSF concentrations of nimodipine in rats after treatment with the nimodipine continuous intravenous infusion formulation of Example 14

[0126] Consistent levels of nimodipine were observed in the CSF over the duration of a single dose of 0.73 mg infusion administered over 4 hours. The range of nimodipine CSF levels measured was 1.26-1.56 ng / ml. Nimodipine CSF concentrations were consistent within 1 hour of infusion. The CSF / plasma ratio was found to be consistent for up to 4 hours, ranging from 0.0064-0.0075. In Tables 14 and Figure 8 Plasma and CSF concentrations of nimodipine in rats following treatment with a continuous intravenous infusion formulation of nimodipine are reported in .

[0127] The oral bioavailability of nimodipine in this study averaged 22% due to high first-pass metabolism. During oral treatment, the plasma concentrations and the shape of the concentration curves varied considerably between rats, probably reflecting variability in first-pass elimination, which also reflects the low average oral bioavailability of nimodipine.

[0128] The absolute bioavailability of nimodipine after continuous intravenous infusion is 100%. The increased bioavailability of the IV infusion formulation also leads to reduced pharmacokinetic variability. In addition, avoiding the first-pass effect after intravenous infusion has the potential to reduce the impact of drug-drug interactions related to CYP3A4 induction or inhibition. Fig. 9 The standard deviation (SD) of nimodipine plasma concentrations in rats when treated with nimodipine continuous intravenous infusion and the reference oral solution are reported in . Table 15

[0129] It can be concluded that when the stable micellar nimodipine formulation of the present invention is administered by continuous intravenous infusion, first-pass metabolism through the liver is minimized and thus bioavailability is improved. Thus, consistent nimodipine levels are maintained in plasma and CSF. Example 17 (Stability)

[0130] The decomposition of nimodipine in the formulations of Examples 3 and 14 was studied at different dissolved oxygen levels and the nimodipine formulations were autoclaved with / without degassing and replacement of the headspace with inert gas to understand its impact on the manufacturing and filling process.

[0131] A series of experiments were performed to evaluate the role of headspace and dissolved oxygen on oxidative drug degradation in nimodipine formulations.

[0132] In the first experiment, 95% ethanol was used during formulation preparation, there was no inert gas blanket, and the WFI in the formulation of Example 3 was not degassed (the process of removing dissolved oxygen from water by inert gas permeation). The results are provided in Table 16.

[0133] In the second experiment, 95% ethanol in WFI under an inert gas blanket and degassed was used in the preparation of the formulation of Example 3. Samples were analyzed by HPLC before and after the autoclave process. The samples were analyzed using the HPLC method to observe the formation of pyridine analog impurities due to oxidative drug degradation before and after autoclave. The results are provided in Table 16.

[0134] In the third experiment conducted, 100% ethanol was used for the formulation of Example 14. The preparation and all other conditions were the same as in Experiment 2. The formulation solution was filtered through a 0.22u PVDF filter and samples were analyzed before and after the autoclave process. The results are provided in Table 16. Table 16

[0135] From the results provided in Table 16, it can be seen that in the first experiment, the formation of pyridine impurity was observed under both conditions, at 0.06% and 0.15%, respectively. After blanketing with inert gas before sealing the vials and subsequent autoclaving of the sealed vials, a reduction in the pyridine analog impurity from 0.15% to 0.08% was observed.

[0136] As can be seen from the results provided in Table 16, in the second experiment, no oxidative degradation of the drug was observed and no pyridine analog impurity was detected.

[0137] As can be seen from the results provided in Table 16, in the third experiment, the nimodipine formulation did not undergo oxidative degradation as observed by the absence of the pyridine analog impurity.

[0138] These experimental studies clearly demonstrated that headspace oxygen and dissolved oxygen levels play an important role in oxidative drug degradation of nimodipine formulations. Degassed WFI used for formulation preparation and inert gas blanketing during processing and filling provided a robust, stable nimodipine IV drug formulation. Example 18

[0139] A PK study was completed at a single center in Canada using a 2-period crossover design in which each subject received either IV GTX-104 first, followed by oral nimodipine; or oral nimodipine first, followed by IV GTX-104. Fifty-eight (58) healthy subjects were randomized in a 1:1 ratio between IV nimodipine infusion formulations prepared according to applicant's prior patent application USSN 15 / 485,813 (now U.S. Patent No. 10,092,557). (Treatment A: nimodipine IV infusion over 72 hours, in addition to a continuous infusion of 0.15 mg / hour nimodipine over 72 hours, plus 4 mg nimodipine infused over 30 minutes every 4 hours) versus Treatment B (Nimoton: nimodipine oral capsules, 60 mg (two 30 mg capsules administered every 4 hours with 240 mL of water for 72 hours). A total of 56 and 55 subjects were included in the PK analysis in Phase 1 and Phase 2, respectively, as two subjects did not complete one of the two phases and one subject was excluded due to protocol deviation. The morning of Day 4 (e.g., 8:00 AM time point) will be the endpoint for the 0.15 mg / h continuous infusion and the 4 mg dose will not be administered.

[0140] The composition of the IV nimodipine injection formulation used in Example 18 is as follows: Table 17 - Composition of Nimodipine Injection Concentrate (2 mg / mL) qs = sufficient quantity; USP = United States Pharmacopeia

[0141] The composition is similar to the composition described in Table 7 Example 14.

[0142] Blood samples were collected at pre-determined time points and nimodipine concentrations were measured using a validated assay to characterize and compare the IV and oral PK profiles. The primary PK endpoint was the maximum concentration (expressed as C max ) and day 3 (AUC Day 3,0-24hr ) The total amount of nimodipine in the blood (expressed as the area under the curve (AUC)). The secondary endpoint was C max . As prospectively defined in SAP, the log-transformed PK parameters for these three endpoints were statistically analyzed using an analysis of variance (ANOVA) model. The IV / oral ratio for each endpoint is presented with the corresponding 90% confidence interval (CI). A ratio of 1 indicates no absolute difference between IV nimodipine infusion and oral nimodipine. If the study is repeated, the 90% CI is the range within which the IV / oral ratio is expected to fall (9 out of 10 times).

[0143] The IV / oral ratios (%) and their corresponding 90% CIs (ranges) for the primary and secondary endpoints among the 56 subjects who completed each treatment period were as follows: Day 1 C max :92%(82-104);AUC 第3天,0-24hr : 106% (99-114); Day 3 C max : 92% (85-101). More specifically, the pharmacokinetic results were as follows: IV infusion of C max第1天，0-4hr is 63.086 and 68.595, the ratio is 91.968 (81.663-103.574)*; AUC of oral nimodipine 第3天,0-24hr 491.630 and 462.116, with a ratio of 106.387 (99.246-114.041), and C max第3天,0-24hr The C of oral nimodipine was 77.5 ng / ml. max第3天,0-24hr The ratio is 85 ng / ml and 92.118 (84.721-100.16). *Geometric least squares mean (C max =ng / mL, AUC = h*ng / mL)**IV / oral geometric mean: % (90% CI). Note: There was no statistical difference in the three parameters (p>0.107). Fig.10(Pharmacokinetics - Day 1) and Fig.11 (Pharmacokinetics - Day 3) shown.

[0144] All three endpoints demonstrated that there were no statistically significant differences in exposure between IV and oral nimodipine over the specified time periods for maximum and total exposure. Plasma concentrations obtained after IV dosing are significantly less variable between subjects than those obtained from capsules administered orally because IV dosing is less sensitive to some of the physiological processes that affect oral dosing, such as taking the drug with or without food, variable GI transit times, variable drug uptake from the gastrointestinal tract (GI tract) to the systemic circulation, and variable hepatic blood flow and hepatic first-pass metabolism. Previous studies have shown that these processes can significantly affect the oral bioavailability of nimodipine and, thus, result in greater intra- and inter-subject variability in oral dosing. Based on the two primary PK endpoints (C max第1天0-4hr , AUC D第3天0-24hr ) and a secondary endpoint (C max第3天0-24hr ), the bioavailability of IV nimodipine is superior to that of oral nimodipine. The diurnal variation associated with IV nimodipine is approximately half that seen with oral nimodipine. No serious AEs (adverse events) or AEs leading to discontinuation occurred after administration of the IV nimodipine formulation.

[0145] Compared with IV nimodipine infusion preparations, the bioavailability of oral nimodipine capsules was observed to be only 7.2%. In addition, the diurnal variation associated with IV nimodipine is about half of that seen with oral nimodipine capsules. Diurnal variation takes into account changes in body function (blood flow, renal function, and liver metabolism) over a one-day course of treatment. The dose of oral nimodipine administered is 60 mg x 18 doses = 1080 mg; the IV dose of IV nimodipine solution preparation is 4 mg x 18 doses + 0.15 mg / h x 72 hours = 82.8 mg.

[0146] No serious adverse events and adverse events (AEs) leading to discontinuation were reported during the study. As expected in a Phase I trial conducted in healthy volunteers, more events related to administration / sampling site were reported with IV GTX-104 (41% vs. 11% with oral administration). Oral nimodipine was associated with more gastrointestinal disorders (16% vs. 7% with IV administration). The other most frequently reported AEs (IV / oral) were headache (36% / 36%), somnolence (9% / 13%), and hot flashes / flushing (10% / 11%). Example 19

[0147] A validated population PK ("popPK") model was used to simulate an alternative bioequivalent dosing regimen consisting of a single bolus followed by a continuous infusion. After several dose ranges of discovery simulations were performed in healthy volunteers, a single 4.5 mg bolus, infused over 30 minutes, followed by a continuous infusion of 1.2 mg / hr was found to be bioequivalent to oral nimodipine every 4 hours. The population profile for this bridging strategy was derived from the weight and age distribution in the PK study described in Example 18. The predicted AUC and C are shown in Table 18. max The graphs of the day 1 curve and day 3 curve in healthy volunteers are shown in Figure 2. Fig.12 and Fig.13 This popPK modeling data was used to inform dosing regimens in patients with subarachnoid hemorrhage. Fig.12 and Fig.13 In the figures, the solid line is the median curve and the shaded areas are the 95% prediction intervals. Abbreviations: IV = intravenous; PO = oral administration (per os). Table 18 - Predicted PK parameters following continuous infusion of 4.5 mg over 30 minutes followed by 1.2 mg / h IV and 60 mg q4 hours oral administration (PO) Example 20

[0148] Based on good modeling practices outlined in the recent FDA guidance on population PK modeling, a popPK analysis of nimodipine following oral and IV infusion was performed to select the best-matched PK model for patients with subarachnoid hemorrhage (SAH) who received 60 mg oral nimodipine on day 1 C. max and AUC on day 3 24h Matching IV dosing regimen.

[0149] To achieve this goal, clinical data from existing PK studies were used to develop a preliminary popPK model, which was refined by incorporating covariates from healthy volunteers and literature data (covariates from aSAH patients) to make the model more robust and better predictive of the PK profile expected in aSAH patients.

[0150] Using this PopPK model, an initial single IV bolus dose infused over 30 minutes followed by a continuous infusion was simulated for a virtual patient population. These IV doses were compared to oral exposures in healthy volunteers, and patients were simulated to account for potential inter-individual differences in covariates and other factors. Sensitivity analysis of the EBE (Empirical Bayesian Estimation) values ​​in the two administration route models was explored.

[0151] The simulation results showed that an IV dose of 3.6 mg over 30 minutes followed by an infusion of 1.2 mg / hr was found to be bioequivalent to the reference (60 mg PO q 4 hours). The plots of the Day 1 and Day 3 curves are shown in Figures 1 and 2, respectively. Fig.14 and Fig.15 The results of the simulations are shown in Tables 19 and 20. The steady state concentrations are predicted to be 20.7 ng / mL for PO and 23.2 ng / mL for IV. Abbreviations: IV = intravenous; PO = oral (per os). The line is the median and the shaded area is the 95% prediction interval. Table 19 - Predicted Day 1 C by Route for Proposed Regimens for Patients with Subarachnoid Hemorrhage max (ng / mL) Table 20 - Predicted Day 3 AUC (ng*hr / ml) by Route for Proposed Regimens in Patients with Subarachnoid Hemorrhage in conclusion

[0152] It will be apparent to those skilled in the art that different but equivalent methods may be used to prepare nimodipine concentrates and diluted formulations, and that these formulations may use other surfactants, carriers and emulsifiers than those specifically mentioned herein. Such solubilized formulations are considered to be within the scope of the appended claims.

Claims

1. A method of providing an IV nimodipine infusion regimen in a human comprising administering (i) a continuous infusion of nimodipine over a period of at least 24 hours, supplemented with (ii) a higher bolus dose of nimodipine at set intervals over a period of at least 24 hours, such that the 24-hour AUC and C of nimodipine are within the dosage regimen of max The dose is equivalent to oral nimodipine.

2. The method of claim 1, wherein the constant nimodipine infusion is about 0.15 mg / hour of nimodipine infused by IV administration over a 24 hour period, supplemented with a higher bolus dose of nimodipine of about 4 mg of nimodipine infused over about 30 minutes at about 4 hour intervals, such that the IV nimodipine infusion regimen is comparable to the 24 hour area under the curve and 24 hour C of 60 mg nimodipine oral capsules administered at about 4 hour intervals over the course of a day. max Equivalent.

3. The method of providing an IV nimodipine infusion regimen of claim 1, which can be achieved by: (i) using a single programmable infusion pump, or (ii) using two infusion pumps with controllable delivery rates to provide a constant infusion of nimodipine throughout a 24-hour period, or (iii) using a single programmable infusion pump to provide a constant infusion of nimodipine throughout a 24-hour period, supplemented with manually administered bolus doses of nimodipine at intervals of about 4 hours, supplemented with 30-minute infusions of nimodipine at intervals of about 4 hours, such that the IV nimodipine infusion regimen is consistent with the 24-hour area under the curve and 24-hour C of the desired dose of nimodipine administered orally (e.g., as an oral capsule) at intervals of about 4 hours over the course of a day. max Equivalent.

4. The method of providing an IV nimodipine infusion regimen of claim 3, wherein 27.6 mg of IV nimodipine provides a 24-hour plasma nimodipine exposure that is equivalent to 360 mg of oral nimodipine and provides a similar pulsatile concentration-time profile.

5. The method of providing an IV nimodipine infusion regimen of claim 4, wherein the infusion rate can be halved to provide a sustained nimodipine dose of about 0.075 mg / hour and a bolus nimodipine dose of about 2 mg administered over about 30 minutes at intervals of about 4 hours to provide an equivalent plasma exposure as 30 mg every 4 hours of oral nimodipine capsules.

6. The method of claim 1 for providing an IV nimodipine infusion regimen that provides an effect selected from the group consisting of: (i) a more reproducible nimodipine plasma profile over the course of a day; (ii) less diurnal variation between morning and evening concentrations; (iii) less likelihood of being compromised by reduced or lost gastrointestinal motility or patient coma; (iv) more rapid response to dose adjustments if drug-related side effects (e.g., hypotension) occur during a course of treatment; and (v) any combination of the foregoing.

7. The method of providing an IV nimodipine infusion regimen of claim 1, wherein the human is a patient suffering from a condition selected from the group consisting of aneurysm, subarachnoid hemorrhage, vasospastic angina, variant angina, stable angina, acute myocardial infarction, myocardial arrest, arrhythmia, systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery surgery, and hypertrophic cardiomyopathy.

8. The method of providing an IV nimodipine infusion regimen of claim 1, comprising continuously infusing an intravenous nimodipine solution according to the present invention over a period of about three weeks.

9. The method of claim 2, providing the IV / oral ratios (%) and their corresponding 90% CIs (ranges) for the primary and secondary endpoints in human subjects completing each treatment period as follows: Day 1 C max : About 92% (82-104); AUC 第3天,0-24hr : about 106% (99-114); and day 3 C max :92%(85-101).

10. The method of providing an IV nimodipine infusion regimen in a human according to claim 1, comprising administering a bolus infusion of about 3.6 mg nimodipine over about 30 minutes, followed by a continuous nimodipine infusion of about 1.2 mg / hour IV for up to 21 days for the treatment of subarachnoid hemorrhage.

11. The method of providing an IV nimodipine infusion regimen in a human according to claim 1, comprising administering a bolus infusion of about 4.5 mg nimodipine over about 39 minutes, followed by a continuous nimodipine infusion of about 1.2 mg / hour IV, wherein the human is a healthy volunteer.

12. The method of claim 1, wherein the continuous nimodipine infusion is about 0.05 mg / hour to about 1.5 mg / hour and is supplemented with (ii) a higher bolus dose of nimodipine at set intervals over a 24 hour period, wherein the higher bolus dose is about 1 mg to about 8 mg of nimodipine administered over a period of about 20 minutes to about 50 minutes.

13. The method of claim 1 for providing an IV nimodipine infusion regimen in a human patient comprising administering (i) a continuous nimodipine infusion of about 0.05 mg / hour to about 1.5 mg / hour over 24 hours supplemented with (ii) a higher bolus dose of nimodipine at set intervals over 24 hours, wherein the human is a patient suffering from a condition selected from the group consisting of aneurysm, subarachnoid hemorrhage, vasospastic angina, variant angina, stable angina, acute myocardial infarction, myocardial arrest, cardiac arrhythmia, systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery surgery, and hypertrophic cardiomyopathy.

14. The method of claim 13, wherein the 24-hour AUC and C of nimodipine in the IV nimodipine infusion regimen are max Equivalent to an oral nimodipine dose selected from 30 mg or 60 mg nimodipine administered every 4 hours.

15. The method of claim 13, wherein the IV nimodipine infusion regimen in the human patient is selected from the group consisting of: (i) a bolus nimodipine dose of about 4.15 mg administered over about 30 minutes, followed by a continuous nimodipine dose of about 0.15 mg / hour for 3.5 hours, repeating this sequence as many times as needed; (ii) providing a continuous nimodipine dose of about 0.075 mg / hour and a bolus nimodipine dose of about 2 mg administered over about 30 minutes at about 4 hour intervals, repeating this sequence as many times as needed; and (iii) a bolus infusion of about 3.6 mg nimodipine over about 30 minutes, followed by a continuous nimodipine infusion of about 1.2 mg / hour for up to 21 days.

Images